CN112955748A - Methods of treating cancer - Google Patents

Methods of treating cancer Download PDF

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CN112955748A
CN112955748A CN201980070604.4A CN201980070604A CN112955748A CN 112955748 A CN112955748 A CN 112955748A CN 201980070604 A CN201980070604 A CN 201980070604A CN 112955748 A CN112955748 A CN 112955748A
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patient
bcma
antigen binding
binding protein
sample
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E.J.德特曼
J.奥帕林斯卡
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GlaxoSmithKline Intellectual Property Development Ltd
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G01N33/57488—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites involving compounds identifable in body fluids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2878—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Abstract

The present invention relates to a method of treating cancer in a patient in need thereof, e.g., in a human subject, comprising determining the level of soluble BCMA (sbbcma) in a sample from the patient and administering to the patient an effective amount of a BCMA antigen binding protein, thereby treating cancer in the patient. Also provided are kits for treating cancer comprising means for determining the level of scbcma in a sample from a patient.

Description

Methods of treating cancer
Technical Field
The present invention relates generally to the treatment of human diseases, for example to the treatment of cancer. More specifically, the invention relates to the use of serum levels of soluble BCMA (sbbcma) to identify patients more likely to respond to BCMA antigen binding proteins in the treatment of cancer.
Background
Effective treatment of hyperproliferative diseases, including cancer, is a continuing goal in the field of oncology. In general, cancer results from deregulation of the normal processes that control cell division, differentiation and apoptotic cell death, and is characterized by the proliferation of malignant cells that have the potential for unlimited growth, local expansion and systemic metastasis. Deregulation of normal processes involves abnormalities in signal transduction pathways and factors that respond differently than those found in normal cells.
B Cell Maturation Antigen (BCMA) is a tumor necrosis superfamily of cell surface receptors required for plasma cell survival. The normal function of BCMA is to promote the survival of B cells at a later stage of differentiation, including plasma cells. Mice lacking BCMA expression demonstrate a reduced number of long-lived bone marrow plasma cells, but have an otherwise normal phenotype. BCMA membrane expression is present on a subset of normal late B cells and is universally detected on normal and malignant plasma cells, including Multiple Myeloma (MM) cells.
The development and use of targeted therapies for cancer treatment reflects a constant understanding of key oncogenic pathways, and how targeted perturbation of these pathways corresponds to clinical response. The difficulty in predicting efficacy against targeted therapies may be a consequence of limited global knowledge of the causative mechanisms of pathway deregulation (e.g., activating mutations, amplification). Treating a selected patient population may help to maximize the potential for therapy. There remains a need to determine the prognosis of patients with B cell disorders, such as multiple myeloma, in order to select the best treatment plan for an individual patient.
Summary of The Invention
The present invention provides methods for diagnosing, determining the prognosis of, or optimizing a treatment plan for a cancer patient by determining the presence or amount of soluble BCMA expression in a patient sample. It has been found that expression of soluble BCMA can be used as a biomarker to diagnose or determine prognosis in cancer patients. In addition, it has been found that the presence or expression level of soluble BCMA in cancer patients can be used to select certain patient populations for treatment with BCMA antigen binding proteins, as well as to inform dosing and treatment regimens by clinicians.
In one embodiment, the present invention provides a method of diagnosing cancer in a patient comprising: (a) obtaining a sample from a patient; and (b) testing the sample for the presence of soluble BCMA expression, wherein the patient is determined to have cancer if the patient expresses soluble BCMA at a high level or expresses sbbcma.
In one embodiment, the present invention provides a method for determining the prognosis of a cancer in a patient, comprising: (a) obtaining a sample from a patient; and (b) testing the sample for the presence of soluble BCMA expression; wherein the prognosis of the patient is poor if the patient has expression of soluble BCMA.
In another embodiment, the invention provides a method for determining the prognosis of a cancer in a patient, comprising: (a) obtaining a sample from a patient; and (b) testing the sample for soluble BCMA expression levels; wherein the prognosis of the patient is poor if the patient has a high level of soluble BCMA expression.
In one embodiment, the invention provides a method of predicting a patient's response to treatment with a BCMA antigen binding protein comprising: (a) obtaining a sample from a patient; and (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses high levels of soluble BCMA, the patient is predicted not to respond to treatment with the BCMA antigen binding protein.
In another embodiment, the present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from a patient; and (b) testing the sample for soluble BCMA expression; and (c) administering to the patient an effective amount of a BCMA antigen binding protein if the subject expresses soluble BCMA.
In yet another embodiment, the present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from a patient; and (b) testing the sample for soluble BCMA expression level; (c) administering to the patient an effective amount of a BCMA antigen binding protein if the patient has a high level of soluble BCMA expression.
Also provided are methods for selecting BCMA antigen binding protein doses for treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from the patient; (b) testing the sample for solubility; and MA expression level; and is
And (c) if the patient has low levels of soluble BCMA expression, treating the patient with a low dose of BCMA antigen binding protein; alternatively, if the patient has a high level of soluble BCMA expression, treating the patient with a high dose of BCMA antigen binding protein.
In one embodiment, the patient is a human patient or a human subject.
In one aspect of the invention, the cancer is selected from the group consisting of: multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.
In another aspect of the invention, the sample obtained from the patient is a serum sample or a blood sample.
The present invention provides BCMA antigen binding proteins selected from the group consisting of antibodies, antibody fragments, bispecific antibodies, antibody-drug-conjugates, bispecific T cell binding agents (BITE), or chimeric antigen receptor T cells (CAR-T).
In one aspect of the invention, the BCMA antigen binding protein is a monoclonal antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO. 7; and a VL comprising the amino acid sequence set forth in SEQ ID NO 8, wherein the antibody is conjugated to MMAF.
In certain aspects, the patient is further treated with at least one additional anti-tumor agent in addition to the BCMA antigen binding protein. In one embodiment, the at least one additional neoplastic agent is selected from the group consisting of: anti-PD 1 antibodies (e.g., nivolumab or pembrolizumab), anti-ICOS and anti-OX 40 antibodies, anti-CD 38 antibodies (e.g., daratuzumab), proteasome inhibitors (e.g., bortezomib, carfilzomib or isazomi), thalidomide analogs (e.g., lenalidomide or pomalidomide) and dexamethasone.
The invention also provides BCMA antigen binding proteins for use in treating cancer in a patient, wherein the patient is characterized by high levels of soluble BCMA expression in a sample from the patient. In another embodiment, the invention provides a BCMA antigen binding protein for use in treating cancer in a patient, wherein the patient expresses soluble BCMA in a sample from the patient.
In another embodiment, the invention contemplates a pharmaceutical composition comprising a BCMA antigen binding protein and at least one pharmaceutically acceptable excipient for use in treating cancer in a patient, wherein the patient is characterized by high levels of soluble BCMA expression in a sample from the patient. In another embodiment, the present invention provides a pharmaceutical composition comprising a BCMA antigen binding protein and at least one pharmaceutically acceptable excipient for use in treating cancer in a patient, wherein the patient expresses soluble BCMA in a sample from the patient.
The present invention provides a kit for treating cancer with a BCMA antigen binding protein in a patient comprising means (means) for determining the level of soluble BCMA in a sample from said patient.
The invention also provides the use of a BCMA antigen binding protein in the manufacture of a medicament for treating cancer in a patient, wherein a sample obtained from said patient is determined to express soluble BCMA. In another embodiment, the use of a BCMA antigen binding protein in the manufacture of a medicament for treating cancer in a patient, wherein a sample obtained from said patient is determined to have high levels of soluble BCMA expression.
Brief Description of Drawings
Figure 1 shows an exemplary assay for detecting sBCMA. Figure 1a shows an exemplary method for detecting free sBCMA (sBCMA does not bind to BCMA antigen binding protein). FIG. 1b shows an exemplary method for detecting bound sBCMA (sBCMA binds to J6M0-MMAF-BCMA antigen binding protein).
Figure 2 shows baseline soluble BCMA levels in healthy patients, multiple myeloma patients, and patients enrolled in the clinical study.
Figure 3 shows the best confirmed response obtained for each patient treated with BCMA antigen binding protein relative to baseline measurements of sbbcma.
Figure 4 shows the reduction of free sBCMA relative to the dose level of BCMA antigen binding protein administered.
Detailed Description
The present invention provides methods for diagnosing, determining the prognosis of, or optimizing a treatment plan for a cancer patient by determining the presence or amount of soluble BCMA expression in a patient sample. It has been found that expression of soluble BCMA can be used as a biomarker to diagnose or determine prognosis in cancer patients. In addition, it has been found that the presence or expression level of soluble BCMA in cancer patients can be used to select certain patient populations for treatment with BCMA antigen binding proteins, as well as to inform dosing and treatment regimens by clinicians.
In one embodiment, the patient is a human patient or a human subject.
Without being bound by theory, it is believed that sBCMA can bind to and inhibit the action of therapeutic BCMA antigen binding proteins that are intended to target BCMA receptors that bind to tumor cells.
B Cell Maturation Antigen (BCMA)
B cell maturation antigen ("BCMA" or "TNFRSF 17") is a plasma cell-expressed type II transmembrane receptor that is a member of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF). It is responsible for driving B cell maturation to long-lived plasma cells and is a potent activator of the nuclear factor Kappa light chain enhancer (NFKB) that activates B cells. NFKB is a family of transcription factors activated by pro-inflammatory cytokines or cell binding ligands, such as BCMA. Activation of this factor is associated with B cell proliferation, survival, differentiation and apoptosis (Bossen and Schneider, 2006). BCMA signaling has been implicated as a factor in supporting the long-lived nature of malignant plasma cells. This has led to BCMA being a potential target for various plasma cell cancers, such as multiple myeloma.
Human BCMA contains the amino acid sequence of Genbank accession No. Q02223.2(SEQ ID NO:11), or a gene encoding human BCMA having at least 90% homology or at least 90% identity to SEQ ID NO: 11:
MLQMAGQCSQNEYFDSLLHACIPCQLRCSSNTPPLTCQRYCNASVTNSVKGTNAILWTCLGLSLIISLAVFVLMFLLRKINSEPLKDEFKNTGSGLLGMANIDLEKSRTGDEIILPRGLEYTVEECTCEDCIKSKPKVDSDHCFPLPAMEEGATILVTTKTNDYCKSLPAALSATEIEKSISAR
soluble BCMA
BCMA can form soluble or secreted forms ("soluble BCMA" or "sBCMA") (Rennert 2000). Without being bound by theory, it is believed that the extracellular portion of the BCMA receptor is cleaved from the membrane on the plasma cell surface by enzymes such as β -secretase (Laurent 2015). Soluble forms of BCMA can be readily detected in human blood samples. As described herein, it has been found that sBCMA can be used as a biomarker for predicting patient outcome, determining prognosis and optimizing treatment plans for cancer patients (e.g., B cell cancers such as multiple myeloma and various lymphomas).
In one embodiment, the present invention provides soluble BCMA for use as a biomarker in a diagnostic method comprising (a) obtaining a sample from a patient; and (b) testing the sample for the presence of soluble BCMA expression. In one embodiment, the patient is determined to have cancer if the patient expresses soluble BCMA at high levels or expresses sbbcma. In another embodiment, when the amount of scbcma is above about 10ng/ml, the patient expresses high levels of BCMA.
Cancer treatment
As used herein, the terms "cancer," "neoplasm," and "tumor" are used interchangeably and, in either the singular or plural, refer to a cell that has undergone malignant transformation that renders it pathological to a host organism. Primary cancer cells can be readily distinguished from non-cancer cells by well-established techniques, particularly histological examination. The definition of cancer cells as used herein includes not only primary cancer cells, but also any cells derived from a cancer cell progenitor. This includes metastasized cancer cells, as well as in vitro cultures and cell lines derived from cancer cells. When referring to a type of cancer that usually manifests as a solid tumor, a "clinically detectable" tumor is one that is detectable based on tumor mass; for example, by a program such as a Computed Tomography (CT) scan, Magnetic Resonance Imaging (MRI), X-ray, ultrasound, or palpation at the time of physical examination, and/or it may be detectable due to expression of one or more cancer specific antigens in a sample obtainable from the patient. The tumor may be a hematopoietic (or hematologic or blood-related) cancer, such as a cancer derived from blood cells or immune cells, which may be referred to as a "liquid tumor. Specific examples of hematological tumor-based clinical conditions include: leukemias, such as chronic myelogenous leukemia, acute myelogenous leukemia, chronic lymphocytic leukemia, and acute lymphocytic leukemia; plasma cell malignancies such as multiple myeloma, MGUS, and Waldenstrom's macroglobulinemia (Waldenstrom's macroglobulinemia); lymphomas such as non-hodgkin's lymphoma, hodgkin's lymphoma; and the like.
In one aspect, the cancer may be any cancer in which there is an abnormal number of blasts of interest or unwanted cellular proliferation or which is diagnosed as a hematologic cancer (including lymphoid and myeloid malignancies). Myeloid malignancies include, but are not limited to: acute myeloid (or myelocytic or myeloblastic) leukemia (undifferentiated or differentiated), acute promyelocytic (or promyelocytic) leukemia, acute myelomonocytic (or myelomonocytic) leukemia, acute monocytic (or monocytic) leukemia, erythrocytic leukemia and megakaryocytic (or megakaryoblastic) leukemia. These leukemias may be collectively referred to as acute myeloid (or myelogenous) leukemia (AML). Myeloid malignancies also include myeloproliferative disorders (MPDs), which include, but are not limited to: chronic myelogenous (or myeloid) leukemia (CML), chronic myelomonocytic leukemia (CMML), essential thrombocythemia (or thrombocythemia), and polycythemia vera (PCV). Bone marrow malignancies also include myelodysplasia (or myelodysplastic syndrome or MDS), which may be referred to as Refractory Anemia (RA), refractory anemia with excess blasts (RAEB), and refractory anemia with excess blasts in transformation (RAEBT); and Myelofibrosis (MFS) with or without agnogenic myeloid metaplasia.
In one aspect, hematopoietic cancers also include lymphoid malignancies, which can affect lymph nodes, spleen, bone marrow, peripheral blood, and/or extranodal sites. Lymphoid cancers include B-cell malignancies including, but not limited to, B-cell non-Hodgkin's lymphoma (B-NHL). B-NHL can be inert (or low), moderate (or aggressive), or high (highly aggressive). Indolent B-cell lymphomas include: follicular Lymphoma (FL); small Lymphocytic Lymphoma (SLL); marginal Zone Lymphoma (MZL) comprising nodal MZL, extranodal MZL, spleen MZL, and spleen MZL with villous lymphocytes; lymphoplasmacytic lymphoma (LPL); and mucosa-associated lymphoid tissue (MALT or extranodal marginal zone) lymphomas. Moderate B-NHL includes: mantle Cell Lymphoma (MCL), diffuse large cell lymphoma (DLBCL), follicular large cell (or grade 3 or 3B) lymphoma, and Primary Mediastinal Lymphoma (PML), with or without leukemia. High grade B-NHL includes Burkitt's Lymphoma (BL), Burkitt's like lymphoma, small lytic cell-free lymphoma (SNCCL) and lymphoblastic lymphoma. Other B-NHLs include immunoblastic lymphoma (or immunocytoma), primary effusion lymphoma, HIV-related (or AIDS-related) lymphoma, and post-transplant lymphoproliferative disorder (PTLD) or lymphoma. B cell malignancies also include, but are not limited to: chronic Lymphocytic Leukemia (CLL), prolymphocytic leukemia (PLL), Waldenstrom's Macroglobulinemia (WM), Hairy Cell Leukemia (HCL), Large Granular Lymphocytic (LGL) leukemia, acute lymphoid (or lymphocytic or lymphoblastic) leukemia, and Castleman's disease. NHL may also include: t-cell non-Hodgkin's lymphoma (T-NHL) including but not limited to T-cell non-Hodgkin's lymphoma Not Otherwise Specified (NOS), peripheral T-cell lymphoma (PTCL), Anaplastic Large Cell Lymphoma (ALCL), angioimmunoblastic lymphoid disorder (AILD), nasal Natural Killer (NK) cell/T-cell lymphoma, gamma/delta lymphoma, cutaneous T-cell lymphoma, mycosis fungoides and Sezary syndrome.
In one aspect, the hematopoietic cancer further comprises hodgkin's lymphoma (or disease) which includes classical hodgkin's lymphoma, nodal sclerosing hodgkin's lymphoma, mixed cell hodgkin's lymphoma, Lymphocyte Predominant (LP) hodgkin's lymphoma, nodal LP hodgkin's lymphoma and lymphocyte depleting hodgkin's lymphoma. Hematopoietic cancers also include plasma cell diseases or cancers such as Multiple Myeloma (MM), including stasis-type MM, monoclonal gammopathy of undetermined significance (or unknown), plasmacytoma (bone, extramedullary), lymphoplasmacytoma (LPL), waldenstrom's macroglobulinemia, plasma cell leukemia and primary Amyloidosis (AL). Hematopoietic cancers may also include other cancers with additional hematopoietic cells, including polymorphonuclear leukocytes (or neutrophils), basophils, eosinophils, dendritic cells, platelets, erythrocytes, and natural killer cells. Tissues comprising hematopoietic cells, referred to herein as "hematopoietic cell tissues," including bone marrow; peripheral blood; thymus; and peripheral lymphoid tissue such as spleen, lymph nodes, mucosa-associated lymphoid tissue (e.g., intestine-associated lymphoid tissue), tonsils, Peyer's patches, and appendices, as well as lymphoid tissue associated with other mucous membranes, such as the bronchial linings.
In one aspect, the cancer is selected from head and neck cancer, breast cancer, lung cancer, colon cancer, ovarian cancer, prostate cancer, glioma, glioblastoma, astrocytoma, glioblastoma multiforme, Bannayan-Zonana syndrome, Cowden disease, Lhermitte-Duclos disease, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, kidney cancer, liver cancer, melanoma, pancreatic cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, AML, chronic neutrophilic leukemia, acute lymphoblastic T cell leukemia, astrocytic T cell leukemia, Plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma promyelocytic leukemia, multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, hodgkin's lymphoma, non-hodgkin's lymphoma, lymphoblastic T-cell lymphoma, burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, vulval cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland carcinoma, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, oral cancer, GIST (gastrointestinal stromal tumor), and testicular cancer.
In one aspect, the human has a solid tumor. In one aspect, the tumor is selected from head and neck cancer, gastric cancer, melanoma, Renal Cell Carcinoma (RCC), esophageal cancer, non-small cell lung cancer, prostate cancer, colorectal cancer, ovarian cancer, and pancreatic cancer. In another aspect, the human has a liquid tumor, such as diffuse large B-cell lymphoma (DLBCL), multiple myeloma, Chronic Lymphoblastic Leukemia (CLL), follicular lymphoma, acute myeloid leukemia, and chronic myeloid leukemia.
The present disclosure also relates to methods of treating or lessening the severity of a cancer selected from: brain cancer (glioma), glioblastoma, Bannayan-Zonana syndrome, cowden disease, Lhermite-Duclos disease, breast cancer, inflammatory breast cancer, Wilm's tumor, Ewing's sarcoma, rhabdomyosarcoma, ependymoma, medulloblastoma, colon cancer, head and neck cancer, kidney cancer, lung cancer, liver cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, sarcoma, osteosarcoma, giant cell tumor of bone, thyroid cancer, lymphoblastic T-cell leukemia, chronic myelogenous leukemia, chronic lymphocytic leukemia, hairy cell leukemia, acute lymphoblastic leukemia, acute myelogenous leukemia, chronic neutrophilic leukemia, acute lymphoblastic T-cell leukemia, plasmacytoma, immunoblastic large cell leukemia, mantle cell leukemia, multiple myeloma megakaryocytic leukemia, multiple myeloma, multiple myeloma, Multiple myeloma, acute megakaryocytic leukemia, promyelocytic leukemia, erythroleukemia, malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T-cell lymphoma, Burkitt's lymphoma, follicular lymphoma, neuroblastoma, bladder cancer, urothelial cancer, lung cancer, vulvar cancer, cervical cancer, endometrial cancer, kidney cancer, mesothelioma, esophageal cancer, salivary gland cancer, hepatocellular carcinoma, gastric cancer, nasopharyngeal cancer, oral cancer, GIST (gastrointestinal stromal tumor) and testicular cancer.
In one embodiment of the methods described herein, the cancer comprises multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.
In one embodiment of the methods described herein, the cancer is multiple myeloma.
Treatment and prevention
The term "treatment" and grammatical variations thereof as used herein refers to therapeutic treatment. In reference to a particular condition, treatment means (1) ameliorating the condition or one or more of the biological clinical manifestations of the condition; (2) interfering with (a) one or more points in the biological cascade that causes or contributes to the condition or (b) one or more biological clinical manifestations of the condition; (3) alleviating one or more symptoms, effects or side effects associated with the condition or treatment thereof; or (4) slowing the progression of the condition or one or more of the biological clinical manifestations of the condition. Prophylactic treatment is also contemplated herein. The skilled person will appreciate that "prevention" is not an absolute term. In medicine, "prevention" is understood to mean prophylactic administration of a drug to significantly reduce the likelihood or severity of, or delay the onset of, a condition or its biological clinical manifestations. Prophylactic treatment is appropriate, for example, when the subject is considered to be at high risk of developing cancer, such as when the subject has a strong family history of cancer or when the subject is exposed to carcinogens.
Sample (I)
The sample, e.g., a biological sample used to test or determine soluble BCMA levels, can be any bodily fluid or tissue, including but not limited to serum, blood components, urine, ascites fluid, bone marrow aspirate and saliva. Testing of sbbcma levels can be performed by several techniques known in the art and/or described herein. In some embodiments, the sample is serum.
BCMA antigen binding proteins
The BCMA antigen binding proteins described herein are useful for treating or preventing cancer. By "BCMA antigen binding protein" is meant any protein construct capable of binding and/or neutralizing human BCMA.
The term "antigen binding protein" as used herein refers to proteins, protein fragments, antibodies, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., three specific and bispecific antibodies), antibody fragments, and other protein constructs capable of binding to human BCMA.
The term "monoclonal antibody" as used herein refers to an antibody obtained from a substantially homogeneous population of antibodies, i.e., the individual antibodies comprising the population are identical except for naturally occurring mutations that may be present in minor amounts. Monoclonal antibodies are highly specific for a single antigenic binding site. Furthermore, in contrast to polyclonal antibody preparations which typically include different antibodies directed against different determinants (epitopes), each monoclonal antibody is directed against a single determinant on the antigen.
The antigen binding protein of the present invention may include the heavy chain variable region and the light chain variable region of the present invention, which may be designed as the structure of a natural antibody or a functional fragment or equivalent thereof. Thus, the antigen binding proteins of the invention may comprise a VH region designed as a full length antibody, (Fab')2 fragment, Fab fragment or equivalent thereof (e.g. scFV, diabodies, triabodies or tetrabodies etc.) when paired with a suitable light chain. The antibody may be IgG1, IgG2, IgG3, or IgG 4; or IgM; IgA, IgE or IgD or modified variants thereof. The constant domains of the antibody heavy chains may be selected accordingly. The light chain constant domain may be a kappa or lambda constant domain. Furthermore, antigen binding proteins may include all classes of modifications, e.g., IgG dimers, no longer bind Fc receptors or Fc mutants that mediate C1Q binding. The antigen binding protein may also be a chimeric antibody of the type described in WO86/01533 which comprises an antigen binding region and a non-immunoglobulin region.
The term "variant" as used herein refers to an amino acid sequence having at least one amino acid change as compared to a reference amino acid sequence, and may include, for example, deletions, additions, insertions, translocations, truncations and/or substitutions.
In one aspect of the invention, the antigen binding protein comprises an mAbdAb, dAbmAb, dAb, ScFv, Fab ', F (ab')2, Fv, Fc, Fd, an antibody (diabody), an affibody, a triabody (triabody), a tetrabody, a minibody (minibody), or a minibody (minibody).
In one embodiment, the BCMA antigen binding protein is a bispecific or trispecific antibody.
In one embodiment, the BCMA antigen protein is conjugated to a drug or cytotoxin. In another embodiment, the BCMA antigen binding protein is an Antibody Drug Conjugate (ADC).
In one aspect of the invention, the BCMA antigen binding protein is a bispecific T cell binding agent (BiTE). In another embodiment, the BiTE comprises a fusion protein consisting of two single chain variable fragments (scFV) of different antibodies.
In one aspect of the invention, the BCMA antigen binding protein is CAR-T (chimeric antigen receptor T cell therapeutic). In another aspect, the CAR comprises a binding domain, a transmembrane domain, and an intracellular effector domain. Chimeric Antigen Receptors (CARs) have been developed as artificial T cell receptors to generate new specificities in T cells without the need for binding to MHC-antigen peptide complexes. These synthetic receptors contain a target binding domain that is associated with one or more signaling domains in a single fusion molecule through a flexible linker. The target binding domain is used to target T cells to specific targets on the surface of pathological cells, and the signaling domain contains the molecular machinery for T cell activation and proliferation. A flexible linker that crosses the T cell membrane (i.e., forms a transmembrane domain) allows cell membrane expression of the target binding domain of the CAR. CARs have been successful in allowing the redirection of T cells against antigens expressed at the surface of tumor cells of various malignancies, including lymphomas and solid tumors.
In one aspect of the invention, the antigen binding protein is a humanized or chimeric antibody, in another aspect, the antibody is humanized. In one aspect, the antibody is a monoclonal antibody.
"chimeric antibody" refers to an engineered antibody in which a portion of the heavy and/or light chain is identical to or homologous to corresponding sequences in an antibody derived from a particular donor antibody class or subclass, while the remainder of the chain is identical to or homologous to corresponding sequences in an antibody derived from another species or belonging to another antibody class or subclass, as well as fragments of such antibodies, so long as they exhibit the desired biological activity.
"humanized antibody" refers to a type of engineered antibody having its CDRs derived from a non-human donor immunoglobulin, with the remaining immunoglobulin-derived portions of the molecule being derived from one (or more) human immunoglobulins. In addition, framework support residues can be altered to retain binding affinity. Suitable human acceptor antibodies may be antibodies selected from conventional databases, such as the KABATS database, the Los Alamos database, and the Swiss Protein database, by homology to the nucleotide and amino acid sequences of the donor antibody. Human antibodies characterized by homology (based on amino acids) to the framework regions of the donor antibody may be suitably adapted to provide heavy chain constant regions and/or heavy chain variable framework regions for insertion of the donor CDRs. Suitable acceptor antibodies that provide constant or variable framework regions of the light chain may be selected in a similar manner. It should be noted that the acceptor antibody heavy and light chains need not be derived from the same acceptor antibody.
Exemplary BCMA antigen binding proteins and methods of making the same are disclosed in international publication No. WO2012/163805, which is incorporated by reference herein in its entirety. Additional exemplary BCMA antigen binding proteins include those described in WO2016/014789, WO2016/090320, WO2016/090327, WO2016/020332, WO2016/079177, WO2014/122143, WO2014/122144, WO2017/021450, WO2016/014565, WO2014/068079, WO2015/166649, WO2015/158671, WO2015/052536, WO2014/140248, WO2013/072415, WO2013/072406, WO2014/089335, US2017/165373, WO2013/154760, and WO 2017/060518, each of which is incorporated herein by reference in its entirety.
In one embodiment, the BCMA antigen binding protein has enhanced antibody dependent cell mediated cytotoxicity (ADCC) effector function. The term "effector function" as used herein refers to one or more of: antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) -mediated responses, Fc-mediated phagocytosis and antibody recycling through the FcRn receptor. For IgG antibodies, effector functions, including ADCC and ADCP, are mediated by the interaction of the heavy chain constant region with the Fcgamma receptor family present on the surface of immune cells. In humans, these include fcgamma ii (CD64), fcgamma iii (CD32) and fcgamma iii (CD 16). The interaction between the antigen binding protein bound to the antigen and the formation of the Fc/Fcgamma complex induces a range of effects including cytotoxicity, immune cell activation, phagocytosis and release of inflammatory cytokines.
In another embodiment, the BCMA antigen binding protein described herein inhibits BAFF and/or 4 month to BCMA receptor binding. In another embodiment, the BCMA antigen binding protein described herein is capable of binding FcgammaRIIIA or is capable of having FcgammaRIIIA-mediated effector function.
"CDR" is defined as the antibody complementarity determining region amino acid sequence, which is immunoglobulin heavy and light chain high variable domain. There are three heavy chain and three light chain CDRs (or CDR regions) in the variable portion of an immunoglobulin. Thus, as used herein, "CDR" may refer to all three heavy chain CDRs, or all three light chain CDRs (or both all heavy and all light chain CDRs, if appropriate).
The CDRs provide the majority of the contact residues for binding of the antibody to the antigen or epitope. CDRs of interest in the present invention are derived from donor antibody variable heavy and light chain sequences and include analogs of naturally occurring CDRs that also share or maintain the same antigen binding specificity and/or neutralizing capacity as the donor antibody from which they were derived. The CDR sequences of the antibodies can be determined by the Kabat numbering system.
The terms "VH" and "VL" are used herein to refer to the heavy and light chain variable domains, respectively, of an antibody.
Exemplary BCMA antigen binding proteins are described in WO2012/163805, the disclosure of which is incorporated herein in its entirety.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a heavy chain variable region CDR1 ("CDRH 1"), said heavy chain variable region CDR1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence NYWMH set forth in SEQ ID NO: 1.
In one embodiment, the heavy chain variable region CDR1 ("CDRH 1") comprises an amino acid sequence having one amino acid change (variant) from the amino acid sequence set forth in SEQ ID NO: 1.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a heavy chain variable region CDR2 ("CDRH 2"), the heavy chain variable region CDR2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to amino acid sequence ATYRGHSDTYYNQKFKG set forth in SEQ ID NO: 2.
In one embodiment, the heavy chain variable region CDR2 ("CDRH 2") comprises an amino acid sequence having one amino acid change (variant) from the amino acid sequence set forth in SEQ ID NO: 2.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a heavy chain variable region CDR3 ("CDRH 3"), the heavy chain variable region CDR3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequence GAIYDGYDVLDN set forth in SEQ ID NO: 3.
In one embodiment, the heavy chain variable region CDR3 ("CDRH 3") comprises an amino acid sequence having one amino acid change (variant) from the amino acid sequence set forth in SEQ ID NO: 3.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a light chain variable region CDR1 ("CDRL 1"), the light chain variable region CDR1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequence SASQDISNYLN set forth in SEQ ID NO: 4.
In one embodiment, the light chain variable region CDL1 ("CDR 1") comprises an amino acid sequence having one amino acid change (variant) from the amino acid sequence set forth in SEQ ID NO: 4.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a light chain variable region CDR2 ("CDRL 2"), said light chain variable region CDR2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence YTSNLHS set forth in SEQ ID NO: 5.
In one embodiment, the light chain variable region CDL2 ("CDR 2") comprises an amino acid sequence having one amino acid change (variant) from the amino acid sequence set forth in SEQ ID NO: 5.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a light chain variable region CDR3 ("CDRL 3"), the light chain variable region CDR3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100% sequence identity to amino acid sequence QQYRKLPWT set forth in SEQ ID NO: 6.
In one embodiment, the light chain variable region CDL3 ("CDR 3") comprises an amino acid sequence having one amino acid change (variant) from the amino acid sequence set forth in SEQ ID NO: 6.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a CDRH1, said CDRH1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 1; a CDRH2, the CDRH2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 2; a CDRH3, the CDRH3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 3; a CDRL1, said CDRL1 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 4; a CDRL2, said CDRL2 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 5; and/or a CDRL3, said CDRL3 comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 6.
In one embodiment, the BCMA antigen binding protein is an antibody comprising CDRH1 comprising the amino acid sequence set forth in SEQ ID No. 1; CDRH2 containing the amino acid sequence shown in SEQ ID NO. 2; CDRH3 comprising the amino acid sequence shown in SEQ ID NO. 3; CDRL1 comprising the amino acid sequence shown in SEQ ID NO. 4; CDRL2 comprising the amino acid sequence shown in SEQ ID NO. 5; and CDRL3 comprising the amino acid sequence shown in SEQ ID NO. 6.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a heavy chain variable region ("VH") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 7:
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSS。
in one embodiment, the BCMA antigen binding protein is an antibody comprising a light chain variable region ("VL") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID NO: 8:
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKR。
in one embodiment, the BCMA antigen binding protein is an antibody comprising a VH antibody having an amino acid sequence with at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 7; and VL of an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence shown in SEQ ID NO. 8.
In one embodiment, the BCMA antigen binding protein is an antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO. 7; and VL comprising the amino acid sequence shown in SEQ ID NO. 8. (referred to herein as "J6M 0").
In one embodiment, the BCMA antigen binding protein is an antibody comprising a heavy chain region ("HC") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 9:
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSNYWMHWVRQAPGQGLEWMGATYRGHSDTYYNQKFKGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGAIYDGYDVLDNWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK。
in one embodiment, the BCMA antigen binding protein is an antibody comprising a light chain region ("LC") comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 10:
DIQMTQSPSSLSASVGDRVTITCSASQDISNYLNWYQQKPGKAPKLLIYYTSNLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYRKLPWTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC。
in one embodiment, the BCMA antigen binding protein is an antibody comprising an HC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 9 and an LC comprising an amino acid sequence having at least 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100% sequence identity to the amino acid sequence set forth in SEQ ID No. 10.
In one embodiment, the BCMA antigen binding protein is an antibody comprising an HC comprising the amino acid sequence shown in SEQ ID No. 9 and an LC comprising the amino acid sequence shown in SEQ ID No. 10.
In one embodiment, the BCMA antigen binding protein is conjugated to a drug or cytotoxin. In another embodiment, the BCMA antigen binding protein is an antibody-drug-conjugate (ADC or immunoconjugate). The ADC can include any of the BCMA antigen binding proteins described herein conjugated to one or more cytotoxic agents, e.g., chemotherapeutic agents, drugs, growth inhibitory agents, toxins (e.g., protein toxins, enzymatically active toxins of bacterial, fungal, plant, or animal origin, or fragments thereof), or radioactive isotopes (i.e., radioconjugates).
In one embodiment, the BCMA antigen binding protein is an immunoconjugate having the general structure:
ABP- ((linker) n-Ctx) m
Wherein
ABP is an antigen binding protein
The linker is absent or any cleavable or non-cleavable linker
Ctx is any cytotoxic agent described herein
n is 0,1,2 or 3; and
m is 1,2,3,4,5,6,7,8,9 or 10.
Exemplary cytotoxic agents include auristatins (e.g., monomethyl auristatin e (mmae) or monomethyl auristatin f (mmaf)); sequence selective DNA-sink binding cross-linkers (e.g., Pyrrolobenzodiazepine (PBD)); maytansinoids (maytansinoids) (e.g., DM1 or DM 4); and alpha-amanitin cyclic peptides.
Exemplary linkers include protease cleavable linkers, 6-maleimidocaproyl (6-Maleimidocaproyl) (MC), Maleimidopropanoyl (MP), valine-citrulline (val-cit), alanine-phenylalanine (ala-phe), p-aminobenzyloxycarbonyl (PAB), N-Succinimidyl 4- (2-pyridylthio) valerate (N-Succinimidyl 4- (2-pyridyllthio) pentanoate) (SPP), N-Succinimidyl 4- (N-maleimidomethyl) cyclohexane-1carboxylate (N-Succinimidyl 4- (N-maleimidomethyl) cyclohexane-1carboxylate) (SMCC), 4- (N-maleimidomethyl) cyclohexane-1carboxylate (MCC) and N-Succinimidyl (4-iodo-acetyl) aminobenzoate (SIAB).
In one embodiment, the BCMA antigen binding protein is an immunoconjugate comprising a monoclonal antibody linked to MMAE or MMAF. In another embodiment, the BCMA antigen binding protein is an immunoconjugate comprising a monoclonal antibody linked to MMAE or MMAF through an MC linker, as shown in the structure:
Figure BDA0003037628250000171
in one embodiment, the BCMA antigen binding protein is a monoclonal antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID NO. 7 and a VL comprising the amino acid sequence set forth in SEQ ID NO. 8, wherein the antibody binds MMAF (referred to herein as "J6M 0-MMAF").
Exemplary CAR-T therapeutics include Bb2121 or Bb2127(Celgene/Bluebird), JCARH125 or FCARH143(Celgene/Juno), LCAR-B38M (Nanjing/Janssen/Genscript), MCARH171/ET140(Celgene/Juno/Eureka), DESCARTES-08(Cartesian), KITE-585(Gilead/Kite), and P-BCMA-101 (Poseida).
Exemplary monoclonal antibodies, bispecific antibodies, trispecific antibodies, Duobodies or BiTes include CC-93269/EM801(Celgene/EngMab), AMG 701 or AMG 420(Amgen), JNJ-64007957(Janssen), SEA-BCMA (Seattle genetics), and PF-06863135 (Pfizer).
Exemplary ADCs include MEDI2228 (Medimumone), AMG 224(Amgen), and HDP-101(Heidelberg Max Eder).
One skilled in the art can readily determine an appropriate therapeutically effective dose of BCMA antigen binding protein. As used herein, the term "effective dose" refers to a dose of a drug or pharmaceutical agent that elicits a biological or medical response in a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective dose" refers to any dose that results in improved treatment, cure, prevention, or amelioration of a disease, or side effect, or a decrease in the rate of progression of a disease or disorder, as compared to a corresponding subject that has not received such dose. The term also includes within its scope dosages effective to enhance normal physiological function.
Suitable doses of the BCMA antigen binding proteins described herein may be calculated for the patient based on their weight, e.g. suitable doses may be in the range of about 0.1 to about 20mg/kg, e.g. about 1 to about 20mg/kg, e.g. about 10 to about 20mg/kg or e.g. about 1 to about 15mg/kg, e.g. about 10 to about 15 mg/kg.
In one embodiment, the therapeutically effective dose of the BCMA antigen binding protein is in the range of about 0.03mg/kg to about 4.6 mg/kg. In yet another embodiment, a therapeutically effective dose of a BCMA antigen binding protein is 0.03mg/kg,0.06mg/kg,0.12mg/kg,0.24mg/kg,0.48mg/kg,0.96mg/kg,1.92mg/kg,2.5mg/kg,3.4mg/kg, or 4.6 mg/kg. In another embodiment, the therapeutically effective dose of anti-BCMA antigen binding protein is 1.9mg/kg, 2.5mg/kg or 3.4 mg/kg.
One aspect of the invention provides a BCMA antigen binding protein for use in treating cancer in a patient, wherein the patient is characterized by expression of soluble BCMA in a sample from the patient.
One aspect of the invention provides a BCMA antigen binding protein for use in treating cancer in a patient, wherein the patient is characterized by high levels of soluble BCMA expression in a sample from the patient.
In another aspect, the invention provides BCMA antigen binding proteins for use in treating a patient identified as having high levels of soluble BCMA. In another aspect, the invention provides BCMA antigen binding proteins for use in treating a patient identified as having high levels of soluble BCMA; the level of SBCMA is greater than 10ng/ml, and wherein the BCMA antigen binding protein is at a concentration per human dose/amount of at least about 1.92 mg/kg.
Pharmaceutical composition
One aspect of the invention provides a pharmaceutical composition for treating cancer in a patient comprising a BCMA antigen binding protein and at least one pharmaceutically acceptable excipient, wherein the patient is characterized by expression of soluble BCMA in a sample from the patient.
One aspect of the invention provides a pharmaceutical composition for treating cancer in a patient comprising a BCMA antigen binding protein, at least one pharmaceutically acceptable excipient, wherein the patient is characterized by high levels of soluble BCMA expression in a sample from the patient.
Method and use
The present invention provides a method of diagnosing cancer in a patient comprising: (a) obtaining a sample from a patient; (b) the samples were tested for the presence of soluble BCMA expression. In one embodiment, the patient is determined to have cancer if the patient expresses soluble BCMA at high levels or expresses sbbcma.
In another embodiment, a method of diagnosing cancer in a patient comprises: (a) obtaining a sample from a patient; (b) testing the sample for the presence of soluble BCMA expression, wherein if the patient expresses sbbcma at a high level, the patient is determined to have cancer, wherein the high level of sbbcma is higher than about 5ng/ml, higher than about 10ng/ml, higher than about 20ng/ml, higher than about 30ng/ml, higher than about 40ng/ml, higher than about 50ng/ml, higher than about 60ng/ml, higher than about 70ng/ml, higher than about 80ng/ml, higher than about 90ng/ml, higher than about 100ng/ml, higher than about 200ng/ml, higher than about 300ng/ml, higher than about 400ng/ml, higher than about 500ng/ml, higher than about 600ng/ml, higher than about 700ng/ml, higher than about 800ng/ml, or higher than about 900 ng/ml.
The present invention also provides a method of determining prognosis of cancer in a patient (e.g., a human subject), comprising (a) obtaining a sample from the patient; (b) samples were tested for soluble BCMA expression level. In one embodiment, the prognosis or outcome is poor if the patient expresses soluble BCMA. In another embodiment, the prognosis or outcome is poor if the patient expresses high levels of soluble BCMA.
Cancer prognosis is typically measured using survival. Cancer statistics typically use an overall five-year survival rate. Disease-free survival is the number of people who have no evidence of cancer after treatment. Progression-free survival is the number of people who have been treated for cancer and have no signs of cancer recurrence or have signs of cancer that have remained stable without growth. In another embodiment, the prognosis is poor when the patient has a chance of survival of less than about 70%, about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, less than about 15%, less than about 10%, or less than about 5% using cancer prognosis statistics known to those of skill in the art.
In one embodiment, the prognosis of the patient is poor when the patient expresses any amount of sBCMA. In one embodiment, the prognosis of the patient is poor when the patient expresses any amount of sBCMA compared to a reference sample.
In one embodiment, the prognosis of the patient is poor when the patient expresses high levels of soluble BCMA, wherein the high levels of sbbcma are above about 5ng/ml, above about 10ng/ml, above about 20ng/ml, above about 30ng/ml, above about 40ng/ml, above about 50ng/ml, above about 60ng/ml, above about 70ng/ml, above about 80ng/ml, above about 90ng/ml, above about 100ng/ml, above about 200ng/ml, above about 300ng/ml, above about 400ng/ml, above about 500ng/ml, above about 600ng/ml, above about 700ng/ml, above about 800ng/ml, or above about 900 ng/ml.
In another embodiment, the prognosis of the patient is poor when the patient expresses greater than about 10ng/ml soluble BCMA. In another embodiment, the prognosis for multiple myeloma in a patient is poor when the patient expresses soluble BCMA at greater than about 10 ng/ml.
One aspect of the invention provides a method of predicting a patient's response to treatment with a BCMA antigen binding protein, the method comprising: (a) obtaining a sample from a patient; and (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses soluble BCMA, the patient is predicted not to respond to treatment with the BCMA antigen binding protein.
One aspect of the invention provides a method of predicting a patient's response to treatment with a BCMA antigen binding protein, the method comprising: (a) obtaining a sample from a patient; and (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses high levels of soluble BCMA, the patient is predicted not to respond to treatment with a BCMA antigen binding protein.
The term "response" is known to those skilled in the art. Guidelines for the particular cancer field are known to those of skill in the art and provide a definition of "response" for a given cancer type. For example, "response" may include strict complete remission (sCR), Complete Remission (CR), near complete remission (nCR), Very Good Partial Response (VGPR), Partial Response (PR), and/or Stable Disease (SD). Exemplary guidance for defining response to treatment in multiple myeloma patients is provided by the International Blood and bone Marrow Center transplant Research group (CIBMTR) (see https:// www.cibmtr.org/manuals/fim/1/en/topic/multiple-myelooma-response-criterion, 2018, the disclosure of which is incorporated herein in its entirety). In one embodiment, the response to treatment in multiple myeloma patients is defined as strict complete remission (sCR), Complete Remission (CR), near complete remission (nCR), Very Good Partial Response (VGPR), or Partial Response (PR).
In another aspect, a method of predicting the response of a multiple myeloma patient to treatment with a BCMA antigen binding protein comprises: (a) obtaining a sample from a patient; and (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses less than about 100ng/ml, less than about 90ng/ml, less than about 80ng/ml, less than about 70ng/ml, less than about 60ng/ml, less than about 50ng/ml, less than about 40ng/ml, less than about 30ng/ml, less than about 20ng/ml, less than about 10ng/ml, or less than about 5ng/ml soluble BCMA, the patient is predicted to respond to treatment with a BCMA antigen binding protein.
In another aspect, a method of predicting the response of a multiple myeloma patient to treatment with a BCMA antigen binding protein comprises: (a) obtaining a sample from a patient; and (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses less than about 50ng/ml soluble BCMA, the patient is predicted to respond to treatment with a BCMA antigen binding protein.
In another aspect, a method of predicting the response of a multiple myeloma patient to treatment with a BCMA antigen binding protein comprises: (a) obtaining a sample from a patient; (b) testing the sample for a level of soluble BCMA expression, wherein the patient expresses greater than about 10ng/ml, greater than about 20ng/ml, greater than about 30ng/ml, greater than about 40ng/ml, about 50ng/ml, greater than about 60ng/ml, greater than about 70ng/ml, greater than about 80ng/ml, greater than about 90ng/ml, or greater than about 100ng/ml soluble BCMA, predicting that the patient will not respond to treatment with the BCMA antigen binding protein.
In another aspect, a method of predicting the response of a multiple myeloma patient to treatment with a BCMA antigen binding protein comprises: (a) obtaining a sample from a patient; (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses greater than about 50ng/ml soluble BCMA, the patient is predicted not to respond to treatment with the BCMA antigen binding protein.
In another aspect, a method of predicting the response of a multiple myeloma patient to treatment with a BCMA antigen binding protein comprises: (a) obtaining a sample from a patient; (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses greater than about 40ng/ml soluble BCMA, the patient is predicted not to respond to treatment with the BCMA antigen binding protein.
In another aspect, a method of predicting the response of a multiple myeloma patient to treatment with a BCMA antigen binding protein comprises: (a) obtaining a sample from a patient; (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses greater than about 50ng/ml soluble BCMA, the patient is predicted not to respond to treatment with the BCMA antigen binding protein.
In another aspect, a method of predicting the response of a multiple myeloma patient to treatment with a BCMA antigen binding protein comprises: (a) obtaining a sample from a patient; and (b) testing the sample for a level of soluble BCMA expression, wherein if the patient expresses greater than about 40ng/ml soluble BCMA, the patient is predicted not to respond to treatment with a BCMA antigen binding protein comprising a VH comprising the amino acid sequence set forth in SEQ ID No. 7 and a VL comprising the amino acid sequence set forth in SEQ ID No. 8, wherein the antibody is conjugated to MMAF.
The present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) determining whether the patient expresses soluble BCMA in a sample obtained from the patient, and (b) administering an effective amount of BCMA antigen binding protein to the patient if the patient expresses soluble BCMA.
In one embodiment, the present invention provides a method of treating cancer in a patient in need thereof, comprising determining whether the patient expresses soluble BCMA, wherein if the patient is determined to express soluble BCMA, administering an effective amount of BCMA antigen binding protein to the patient.
In one embodiment, the present invention provides a method of treating cancer in a patient in need thereof, comprising determining whether the patient expresses high levels of soluble BCMA, wherein if the patient is determined to express high levels of soluble BCMA, administering to the patient an effective amount of BCMA antigen binding protein.
The present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) determining whether the patient expresses soluble BCMA in a sample obtained from the patient, and (B) administering an effective amount of BCMA antigen binding protein to the patient if the patient expresses soluble BCMA, wherein the patient is determined to have multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, follicular lymphoma, or diffuse large B-cell lymphoma, and wherein the antigen binds to a VH comprising an amino acid sequence set forth in SEQ ID NO:7 and a VL comprising an amino acid sequence set forth in SEQ ID NO:8, wherein the antibody is conjugated to MMAF.
The present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) determining whether the patient expresses high levels of soluble BCMA in a sample obtained from the patient, and (B) administering an effective amount of BCMA antigen binding protein to the patient if the patient expresses high levels of soluble BCMA. The present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) determining whether a patient expresses soluble BCMA in a sample obtained from the patient, and (B) administering an effective amount of a BCMA antigen binding protein to the patient if the patient expresses high levels of soluble BCMA, wherein the patient is determined to have multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, follicular lymphoma, or diffuse large B-cell lymphoma, wherein the antigen binds to a VH comprising the amino acid sequence set forth in SEQ ID NO:7 and a VL comprising the amino acid sequence set forth in SEQ ID NO:8, wherein the antibody is conjugated to MMAF, and sbbcma expression is high at sbmcca levels of at least about 10 ng/mL.
The present invention provides a method of treating cancer in a patient in need thereof, comprising: (a) determining the level of soluble BCMA in a sample obtained from the patient, and administering to the patient an effective amount of BCMA antigen binding protein if the level of soluble BCMA is high. In one embodiment, the level of sbbcma is high.
The present invention also provides a method for treating cancer in a patient (e.g., a human patient or subject) comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression; and (c) administering an effective amount of a BCMA antigen binding protein to the patient if the patient expresses soluble BCMA, or expresses high levels of soluble BCMA.
In one embodiment, when the patient expresses any amount of sBCMA in the sample, the patient expresses soluble BCMA. In one embodiment, the patient expresses soluble BCMA when the patient expresses any amount of sbbcma in the sample compared to the reference sample.
In another embodiment, the invention also provides a method of treating cancer in a patient (e.g., a human patient or subject) comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression; and (c) administering an effective amount of a BCMA antigen binding protein to the patient if the patient expresses high levels of soluble BCMA, wherein the patient expresses high levels of soluble BCMA when the amount of sbbcma in the sample is above about 5ng/ml, above about 10ng/ml, above about 20ng/ml, above about 30ng/ml, above about 40ng/ml, above about 50ng/ml, above about 60ng/ml, above about 70ng/ml, above about 80ng/ml, above about 90ng/ml, above about 100ng/ml, above about 200ng/ml, above about 300ng/ml, above about 400ng/ml, above about 500ng/ml, above about 600ng/ml, above about 700ng/ml, above about 800ng/ml, or above about 900 ng/ml.
In another embodiment, the invention also provides a method of treating cancer in a patient (e.g., a human patient or subject) comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression; and (c) administering an effective amount of a BCMA antigen binding protein to the patient if the patient expresses high levels of soluble BCMA, wherein the patient expresses high levels of soluble BCMA when the amount of sbbcma in the sample is above about 10 ng/ml.
In another embodiment, the invention also provides a method of treating cancer in a patient (e.g., a human patient or subject) comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression; and (c) administering an effective amount of a BCMA antigen binding protein to the patient if the patient expresses high levels of soluble BCMA, wherein the patient expresses high levels of soluble BCMA when the amount of sbbcma in the sample is above about 10 ng/ml; wherein the cancer is selected from the group consisting of multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.
In another embodiment, the invention also provides a method of treating cancer in a patient (e.g., a human patient or subject) comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression; and (c) administering an effective amount of a BCMA antigen binding protein to the patient if the patient expresses high levels of soluble BCMA, wherein the patient expresses high levels of soluble BCMA when the amount of sbbcma in the sample is above about 10 ng/ml; wherein the cancer is selected from the group consisting of multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma; and wherein the antigen binds to a VH comprising an amino acid sequence set forth in SEQ ID NO. 7 and a VL comprising an amino acid sequence set forth in SEQ ID NO. 8, wherein the antibody is conjugated to MMAF.
The present invention provides a method of selecting a dose of BCMA antigen binding protein for use in treating a patient in need thereof, comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression level; (c) treating the patient with a low dose of BCMA antigen binding protein if the patient's soluble BCMA expression is low; alternatively, if the patient has high soluble BCMA expression, the patient is treated with a high dose of BCMA antigen binding protein.
In one embodiment, the invention provides a method of selecting a dose of BCMA antigen binding protein for use in treating a patient in need thereof, comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression level; (c) treating the patient with a low dose of BCMA antigen binding protein if the patient has low soluble BCMA expression, wherein the patient has low soluble BCMA expression when the amount of soluble BCMA in the sample is below about 300 ng/day. ml, less than about 200ng/ml, less than about 100ng/ml, less than about 90ng/ml, less than about 80ng/ml, less than about 70ng/ml, less than about 60ng/ml, less than about 50ng/ml, less than about 40ng/ml, less than about 30ng/ml, less than about 20ng/ml, less than about 10ng/ml, or less than about 5 ng/ml.
In one embodiment, the invention provides a method of selecting a dose of BCMA antigen binding protein for use in treating a patient in need thereof, comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression level; (c) treating the patient with a low dose of a BCMA antigen binding protein if the patient's soluble BCMA expression is low, wherein the patient has low soluble BCMA expression when the amount of soluble BCMA in the sample is below about 10 ng/hr. And (3) ml.
In one embodiment, the invention provides a method of selecting a dose of BCMA antigen binding protein for use in treating a patient in need thereof, comprising: (a) obtaining a sample from a patient; (b) testing the sample for soluble BCMA expression level; (c) treating the patient with a high dose of BCMA antigen binding protein if the patient has high soluble BCMA expression, wherein the patient has high soluble BCMA expression when the amount of soluble BCMA in the sample is above about 5 ng/day. m1, greater than about 10ng/ml, greater than about 20ng/ml, greater than about 30ng/ml, greater than about 40ng/ml, greater than about 50ng/ml, greater than about 60ng/ml, greater than about 70ng/ml, greater than about 80ng/ml, greater than about 90ng/ml, greater than about 100ng/ml, greater than about 200ng/ml, greater than about 300ng/ml, greater than about 400ng/ml, greater than about 500ng/ml, greater than about 600ng/ml, greater than about 700ng/ml, greater than about 800ng/ml, or greater than about 900 ng/ml.
In one embodiment, the invention provides a method for selecting a dose of BCMA antigen binding protein for treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from the patient; (b) testing said sample for soluble BCMA expression levels; and (c) if the patient has low soluble BCMA expression, treating the patient with a low dose of BCMA antigen binding protein; alternatively, if the patient has high soluble BCMA expression, treating the patient with a high dose of BCMA antigen binding protein.
In one embodiment, the invention provides a method for selecting a dose of BCMA antigen binding protein for treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from the patient; (b) testing said sample for soluble BCMA expression levels; and (c) if the patient has low soluble BCMA expression, treating the patient with a low dose of BCMA antigen binding protein, wherein the patient has low soluble BCMA expression when the amount of soluble BCMA in the sample is less than about 300ng/ml, less than about 200ng/ml, less than about 100ng/ml, less than about 90ng/ml, less than about 80ng/ml, less than about 70ng/ml, less than about 60ng/ml, less than about 50ng/ml, less than about 40ng/ml, less than about 30ng/ml, less than about 20ng/ml, less than about 10ng/ml, or less than about 5 ng/ml.
In one embodiment, the invention provides a method for selecting a dose of BCMA antigen binding protein for treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from the patient; (b) testing said sample for soluble BCMA expression levels; and (c) treating the patient with a low dose of BCMA antigen binding protein if the patient has low soluble BCMA expression, wherein the patient has low soluble BCMA expression when the amount of soluble BCMA in the sample is below about 10 ng/ml.
In one embodiment, the invention provides a method for selecting a dose of BCMA antigen binding protein for treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from the patient; (b) testing said sample for soluble BCMA expression levels; and (c) if the patient has high soluble BCMA expression, treating the patient with a high dose of BCMA antigen binding protein, wherein the patient has high soluble BCMA expression when the amount of soluble BCMA in the sample is above about 5ng/ml, above about 10ng/ml, above about 20ng/ml, above about 30ng/ml, above about 40ng/ml, above about 50ng/ml, above about 60ng/ml, above about 70ng/ml, above about 80ng/ml, above about 90ng/ml, above about 100ng/ml, above about 200ng/ml, above about 300ng/ml, above about 400ng/ml, above about 500ng/ml, above about 600ng/ml, above about 700ng/ml, above about 800ng/ml, or above about 900 ng/ml.
In one embodiment, the invention provides a method for selecting a dose of BCMA antigen binding protein for treating cancer in a patient in need thereof, comprising: (a) obtaining a sample from the patient; (b) testing said sample for soluble BCMA expression levels; and (c) treating the patient with a high dose of BCMA antigen binding protein if the patient has high soluble BCMA expression, wherein the patient has high soluble BCMA expression when the amount of soluble BCMA in the sample is greater than about 10 ng/ml.
In one embodiment, the low dose of BCMA antigen binding protein is less than 4.6 mg/kg. In another embodiment, the low dose of BCMA antigen binding protein is 0.03mg/kg,0.06mg/kg,0.12mg/kg,0.24mg/kg,0.48mg/kg,0.96mg/kg,1.92mg/kg,2.5mg/kg or 3.4 mg/kg.
In one embodiment, the high dose of BCMA antigen binding protein is greater than 0.96 mg/kg. In another embodiment, the high dose of BCMA antigen binding protein is 0.96mg/kg,1.92mg/kg,2.5mg/kg,3.4mg/kg or 4.6 mg/kg.
One aspect of the invention provides the use of a BCMA antigen binding protein in the manufacture of a medicament for treating cancer in a patient, wherein a sample obtained from the patient subject is determined to express soluble BCMA. Another aspect of the invention provides the use of a BCMA antigen binding protein in the manufacture of a medicament for treating cancer in a patient, wherein a sample obtained from the patient is determined to have a high level of soluble BCMA expression.
In one embodiment, when the patient expresses any amount of sBCMA in the sample, the patient expresses soluble BCMA. In another embodiment, the patient expresses high levels of soluble BCMA when the amount of sbbcma in the sample is above about 5ng/mL, above about 20ng/mL, above about 30ng/mL, above about 40ng/mL, above about 50ng/mL, above about 60ng/mL, above about 70ng/mL, above about 80ng/mL, above about 90ng/mL, above about 100ng/mL, above about 200ng/mL, above about 300ng/mL, above about 400ng/mL, above about 500ng/mL, above about 600ng/mL, above about 700ng/mL, above about 800ng/mL, or above about 900 ng/mL.
One aspect of the invention provides use of a BCMA antigen binding protein in the manufacture of a medicament for treating cancer in a patient, wherein a sample obtained from the patient subject is determined to express soluble BCMA; and wherein the patient is determined to have multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-Hodgkin's lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma; and wherein the patient expresses at least about 10ng/ml of sBCMA.
In any of the embodiments described herein, when the patient expresses soluble BCMA at a level of greater than about 5ng/ml, greater than about 10ng/ml, greater than about 20ng/ml, greater than about 30ng/ml, greater than about 40ng/ml, greater than about 50ng/ml, greater than about 60ng/ml, greater than about 70ng/ml, greater than about 80ng/ml, greater than about 90ng/ml, greater than about 100ng/ml, greater than about 200ng/ml, greater than about 300ng/ml, greater than about 400ng/ml, greater than about 500ng/ml, greater than about 600ng/ml, greater than about 700ng/ml, greater than about 800ng/ml, or greater than about 900ng/ml, the patient expresses high levels of soluble BCMA.
In some embodiments, in addition to treatment with a BCMA antigen binding protein, the patient may be further treated with one or more additional cancer therapeutic or anti-tumor agents. In general, any antineoplastic agent active against a susceptible tumor to be treated can be co-administered in the cancer treatment of the present invention. One of ordinary skill in the art will be able to discern which combinations of agents would be useful based on the particular characteristics of the drug and the cancer involved.
Typical antineoplastic agents useful in the present invention include, but are not limited to, antimicrotubule agents or antimitotic agents, such as diterpenoids and vinca alkaloids; a platinum coordination complex; thalidomide analogs (IMiDs); immunotherapeutic antibodies (e.g., anti-PD 1, anti-PDL 1, anti-CD 38, anti-ICOS, anti-OX 40); alkylating agents such as nitrogen mustards, oxazaphosphorines, alkyl sulfonates, nitrosoureas, and triazenes; antibiotics such as actinomycin, anthracyclines and bleomycin; topoisomerase I inhibitors, such as camptothecin; topoisomerase II inhibitors, such as epipodophyllotoxin; antimetabolites such as purine and pyrimidine analogs and antifolate compounds; hormones and hormone analogs; a signal transduction pathway inhibitor; non-receptor tyrosine kinase angiogenesis inhibitors; an immunotherapeutic agent; a pro-apoptotic agent; inhibitors of cell cycle signaling; a proteasome inhibitor; a heat shock protein inhibitor; inhibitors of cancer metabolism; a chemotherapeutic agent; steroids (e.g., dexamethasone); an immunomodulator; an immunomodulator; an immunomodulator; and an immunostimulatory adjuvant.
In one embodiment, the additional anti-neoplastic agent is at least one selected from the group consisting of an anti-PD 1 antibody, an anti-ICOS antibody and an anti-OX 40 antibody, an anti-CD 38 antibody, a proteasome inhibitor, a thalidomide analog and dexamethasone.
One skilled in the art can readily determine the appropriate therapeutically effective dose of the additional cancer therapeutic or antineoplastic agent. As used herein, the term "effective dose" of an additional cancer therapeutic or antineoplastic agent refers to a dose of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for example, by a researcher or clinician. Furthermore, the term "therapeutically effective dose" of an additional cancer therapeutic or antineoplastic agent refers to any dose that results in improved treatment, cure, prevention, or amelioration of a disease, or side effect, or a decrease in the rate of progression of a disease or disorder, as compared to a corresponding subject that has not received such dose. The term also includes within its scope dosages effective to enhance normal physiological function.
Measurement of soluble BCMA
Soluble BCMA in a sample can be measured by various techniques known in the art. The assay can be specific for detecting free circulating soluble BCMA as well as soluble BCMA bound to BCMA antigen binding protein. For example, enzyme-linked immunosorbent assay (ELISA), Western blot assay, mass spectrometry, Meso Scale Discovery (MSD), Immunohistochemistry (IHC), immunoprecipitation, immunofluorescence, flow cytometry or other antibody-based capture/detection methods can be used to measure sBCMA levels in a sample. The various detection moieties may include biotin/streptavidin binding, colorimetric assays, ultraviolet, fluorescent, electrochemical, or other detection methods known to those skilled in the art.
The presence or expression level of scbcma can be determined by comparing a sample of interest to a reference sample or control sample. For example, the reference sample or control sample may be: 1) samples known to be free of sBCMA (e.g., buffer control or samples from healthy donors); 2) a negative control sample, wherein no specific assay reagent is intentionally included to obtain a negative signal; 3) several samples containing different amounts of scbcma for use in a standard curve for quantifying the amount of scbcma in a sample of interest; or 4) as a common practice for those skilled in the art.
In one embodiment, sBCMA is detected in a sample using means for detection comprising a capture antibody and/or a detection antibody that binds to sBCMA (free or bound to a BCMA antigen binding protein) in the sample, wherein the means comprises a detection moiety.
An exemplary assay for detecting sbbcma is demonstrated in figure 1. These assays are further described herein and in example 1.
Figure 1a demonstrates an exemplary method for detecting free sBCMA (sBCMA that does not bind to a BCMA antigen binding protein). In an exemplary embodiment, free sBCMA is detected using the method described in example 1.
Figure 1b demonstrates an exemplary method for detecting sBCMA binding to BCMA antigen binding protein. In an exemplary embodiment, sBCMA that binds to BCMA antigen binding protein is detected using the method described in example 1.
Reagent kit
In one embodiment, a kit for treating cancer is provided comprising means (e.g., reagents) for determining the level of sbbcma in a sample, e.g., a human serum sample, from a patient. In one embodiment, the means for determining the level of sBCMA in a sample comprises a capture antibody and/or a detection antibody that binds to sBCMA in the sample and contains a detection moiety. The kit can include any means described herein for detecting sBCMA in a sample.
Sequence Listing
Figure BDA0003037628250000281
Figure BDA0003037628250000291
Examples
The following examples illustrate various non-limiting aspects of the present invention.
The method comprises the following steps:
in a dose escalation clinical study, 38 subjects were treated with J6M0-MMAF (part 1). The dosage ranges are from 0.03mg/kg up to 4.60mg/kg (0.03mg/kg, 0.06mg/kg, 0.24mg/kg,0.48mg/kg,0.96mg/kg,1.92mg/kg,2.5mg/kg,3.4mg/kg and 4.6 mg/kg). An expanded cohort of 35 subjects followed at a dose of 3.40mg/kg (part 2). An Overall Response Rate (ORR) of 60% (21/35; 95% CI 42.1-76.1) according to the IMWG standard was demonstrated. During these studies, the level of circulating soluble bcma (sbbcma) was followed. Soluble BCMA was measured in serum samples collected before and after infusion of J6M 0-MMAF. The level of free sBCMA (fig. 1a) and J6M0-MMAF bound sBCMA (fig. 1b) was determined using an immunoassay (fig. 1).
Free sBCMA assay protocol (FIG. 1a)
1.1. Preparation of anti-BCMA antibody-coated plate (3. mu.g/ml)
1. Preparation of appropriate volume (approximately 3 mL/plate) of Capture coated antibody-3. mu.g/mL of anti-BCMA antibody in DPBS (J6M0)
2. mu.L of the coating solution was dispensed to each well of a 96-well high binding MSD plate (MSD standard streptavidin coated 96-well plate-Meso Scale Discovery Cat # L11 SA).
3. The MSD plates were covered with a plate sealer and incubated overnight (18 Hr. + -. 3Hr) on flat surfaces in a freezer at 2-8 ℃.
Preparation of huBCMA Standard Curve
1. On the day of the assay, 12-point calibration curves for known amounts of BCMA ranging from 1000ng/ml to 0ng/ml were prepared in BCMA depleted serum.
1.3. Transfer the sample to the plate
1. MSD plates were washed 3 times with wash buffer (1 xPBST).
2. 25 μ L of the dilution standard curve and test sample were transferred to an MSD assay plate. All samples were tested in duplicate.
3. The samples were incubated on a shaker at a speed of about 600rpm for 1 hour (+ -5 min).
1.4. Preparation of detection antibody and reporter
1. 10 minutes before the end of sample incubation, a detection antibody (biotinylated anti-BCMA pAB-R & Dsystems # BAF193) was prepared in antibody diluent at 3. mu.g/mL as follows:
mu.L of BAF193 (50. mu.g/mL) was added to 18. mu.L of streptavidin Sulfo TAG (0.5mg/mL) (Meso Scale Discovery # R32AD-1) + 2802. mu.L of antibody diluent (1% BSA/1 XDPBS).
2. MSD plates were washed 3 times with wash buffer (1 xPBST).
3. Add 25 μ L of detection antibody solution to each well of the assay plate.
4. The plates were covered and placed on a shaker at about 600rpm for 1 hour (. + -. 5min) at room temperature.
1.5. Reading buffer
1. The 1x MSD read buffer was prepared as follows:
5ml 4 XMSD read buffer T (Meso Scale Discovery # R92TC-1) plus 15ml Milli-Q water.
2. MSD plates were washed 3 times with wash buffer (1 xPBST).
3. Transfer 150 μ L of 1 × read buffer to each well of the assay plate.
4. The MSD assay plate was immediately read by using MSD Sector Imager 6000(Meso Scale Discovery).
Bound sBCMA assay protocol (sBCMA binding to J6M 0-MMAF) (FIG. 1b)
2.1 plate coating
1. Biotinylated anti-BCMA pAb (R & D Systems # BAF193) was diluted to a concentration of 50. mu.g/mL in 1 XPBS.
2. mu.L of biotin-BAF 193 (50. mu.g/mL) was added to 5820. mu.l of coating buffer (25mM Hepes/0.015% Triton X-100).
3. Mu.l of the coating solution was dispensed into each well of a MSD standard streptavidin-coated 96-well plate (Meso Scale Discovery Cat # L11 SA).
4. Plates were covered and incubated overnight in a 2-8 ℃ freezer.
2.2. Closing a panel
1. MSD plates were washed with wash buffer (0.1% DPBST).
2. Mu.l of 3% blocking buffer (MSD Blocker A-Meso Scale Discovery # R93BA-4) was transferred to each well on the plate.
3. The plates were covered and placed on a plate shaker (about 600rpm) for 1-2 hours at room temperature.
2.3. Preparation of Standard Curve, sample and QCS for analysis
1. A9-point standard curve of known amounts of BCMA/J6M0-MMAF was prepared in BCMA-depleted serum, ranging from 200ng/mL BCMA/20 μ g/mL J6M0-MMAF to 0ng/mL BCMA/0 μ g/mL J6M 0-MMAF.
2.4. Transfer of samples to assay plates
1. MSD plates were washed with wash buffer (0.1% DPBST).
2. 25 μ L of the dilution standard curve and test sample were transferred to an MSD assay plate. All samples were tested in duplicate.
3. Assay plates were covered and placed on a plate shaker (about 600rpm) at room temperature and incubated for 2 hours ± 5 minutes.
2.5. Detection antibody (sTag anti-auristatin MMAF antibody)
1. The sTag-Ru anti-auristatin MMAF antibody was diluted to 1. mu.g/ml in antibody diluent (1% BSA/1X DPBS). (12. mu.l of sTag anti-auristatin MMAF (0.5mg/ml) was added to 5988ml antibody diluent).
2. MSD plates were washed with wash buffer (0.1% DPBST).
3. Mu.l of sTag anti-auristatin solution was added to each well on the plate.
4. The plates were covered and incubated with shaking (600rpm) for 1 hour + -5 minutes at room temperature.
2.6. Plate reading
1. After about 1 hour, the plates were washed with wash buffer (0.1% DPBST).
2. Mu.l of 2-fold MSD read buffer T (Meso Scale Discovery # R92TC-1) was added to each well of the plate.
3. Plates were read within 10 minutes on MSD SECTOR Imager 6000(Meso Scale Discovery).
Example 1
Soluble BCMA was measured in sera from healthy donors (n-10), from Multiple Myeloma (MM) patients (n-10), and from samples of patients enrolled in the clinical study described herein. Baseline sBCMA levels observed in samples from clinical studies were comparable to those observed in multiple myeloma patients and showed higher levels than those observed in healthy donor sera (figure 2). Examination of circulating sBCMA revealed high levels of sBCMA with a baseline median concentration of free sBCMA of 58ng/ml at all doses (n-68; range 4ng/ml to >1000 ng/ml).
Example 2
Soluble BCMA was measured at baseline (before infusion) from subjects in the dose expansion cohort (part 2). Figure 3 shows the best confirmed response obtained for each patient relative to baseline measurements of sBCMA. The level of baseline sBCMA is typically lower in non-responsive patients (81ng/ml, n-12; compared to 43ng/ml, n-19). High baseline sBCMA levels were also found in responders, with levels as high as 262 ng/mL.
Binding of J6M0-MMAF to sBCMA was measured by comparing the post-infusion levels of free sBCMA measured 60 minutes after the start of infusion with the levels found prior to infusion. Figure 4 shows that the reduction in free sBCMA appears to be related to the dose level administered, and doses above 1.92mg/kg consistently achieved greater than 90% reduction in free sBMCA (percentage change from baseline). The points are colored depending on whether the patient has the best clinical response for PR or better (R), or is a non-responder (NR). The average percent reduction for each dose group is shown as a horizontal black line. Part 1 is the dose escalation group and part 2 is the dose augmentation group.
At higher dose levels, J6M0-MMAF was found to bind most of sBCMA, and a response to J6M0-MMAF was observed in 60% of dose-expanded subjects with low or high baseline sBCMA. Baseline sBCMA was higher in non-responders compared to responders because J6M0-MMAF was bound by soluble BCMA, achieving greater than 90% reduction in free sBCMA as evidenced by doses above 1.92 mg/kg.
Sequence listing
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225 230 235 240
Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
245 250 255
Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His
260 265 270
Glu Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val
275 280 285
His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr
290 295 300
Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly
305 310 315 320
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
325 330 335
Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
340 345 350
Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr Lys Asn Gln Val Ser
355 360 365
Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
370 375 380
Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
385 390 395 400
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val
405 410 415
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
420 425 430
His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
435 440 445
Pro Gly Lys
450
<210> 10
<211> 214
<212> PRT
<213> Artificial sequence
<220>
<223> artificially synthesized sequence
<400> 10
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Ser Ala Ser Gln Asp Ile Ser Asn Tyr
20 25 30
Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Tyr Thr Ser Asn Leu His Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Arg Lys Leu Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys Arg Thr Val Ala Ala
100 105 110
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly
115 120 125
Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala
130 135 140
Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
145 150 155 160
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser
165 170 175
Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys His Lys Val Tyr
180 185 190
Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro Val Thr Lys Ser
195 200 205
Phe Asn Arg Gly Glu Cys
210
<210> 11
<211> 184
<212> PRT
<213> Intelligent people
<400> 11
Met Leu Gln Met Ala Gly Gln Cys Ser Gln Asn Glu Tyr Phe Asp Ser
1 5 10 15
Leu Leu His Ala Cys Ile Pro Cys Gln Leu Arg Cys Ser Ser Asn Thr
20 25 30
Pro Pro Leu Thr Cys Gln Arg Tyr Cys Asn Ala Ser Val Thr Asn Ser
35 40 45
Val Lys Gly Thr Asn Ala Ile Leu Trp Thr Cys Leu Gly Leu Ser Leu
50 55 60
Ile Ile Ser Leu Ala Val Phe Val Leu Met Phe Leu Leu Arg Lys Ile
65 70 75 80
Asn Ser Glu Pro Leu Lys Asp Glu Phe Lys Asn Thr Gly Ser Gly Leu
85 90 95
Leu Gly Met Ala Asn Ile Asp Leu Glu Lys Ser Arg Thr Gly Asp Glu
100 105 110
Ile Ile Leu Pro Arg Gly Leu Glu Tyr Thr Val Glu Glu Cys Thr Cys
115 120 125
Glu Asp Cys Ile Lys Ser Lys Pro Lys Val Asp Ser Asp His Cys Phe
130 135 140
Pro Leu Pro Ala Met Glu Glu Gly Ala Thr Ile Leu Val Thr Thr Lys
145 150 155 160
Thr Asn Asp Tyr Cys Lys Ser Leu Pro Ala Ala Leu Ser Ala Thr Glu
165 170 175
Ile Glu Lys Ser Ile Ser Ala Arg
180

Claims (33)

1. A method for determining prognosis of cancer in a patient, comprising:
(a) obtaining a sample from the patient; and is
(b) Testing the sample for the presence of soluble BCMA expression;
wherein the prognosis of the patient is poor if the patient has expression of soluble BCMA.
2. A method for determining prognosis of cancer in a patient, comprising:
(a) obtaining a sample from the patient; and is
(b) Testing said sample for soluble BCMA expression levels;
wherein the prognosis of the patient is poor if the patient has a high level of soluble BCMA expression.
3. A method of predicting a patient's response to treatment with a BCMA antigen binding protein comprising: (a) obtaining a sample from a patient; and (b) testing said sample for soluble BCMA expression levels, wherein if said patient expresses high levels of soluble BCMA, then said patient is predicted not to respond to treatment with a BCMA antigen binding protein.
4. The method of claim 3, wherein the patient is a multiple myeloma patient, and wherein soluble BCMA expression is high at levels of soluble BCMA expression greater than about 40ng/ml or greater than 50 ng/ml.
5. The method of claim 4, wherein the multiple myeloma patient is predicted not to respond to treatment with a BCMA antigen binding protein comprising a VH comprising the amino acid sequence set forth in SEQ ID NO 7; a VL comprising the amino acid sequence set forth in SEQ ID NO 8, and wherein the antibody is conjugated to MMAF.
6. A method for treating cancer in a patient in need thereof, comprising:
(a) obtaining a sample from the patient; and is
(b) Testing said sample for soluble BCMA expression; and is
(c) Administering to the patient an effective amount of a BCMA antigen binding protein if the subject expresses soluble BCMA.
7. A method for treating cancer in a patient in need thereof, comprising:
(a) obtaining a sample from the patient; and is
(b) Testing said sample for soluble BCMA expression levels; and is
(c) Administering to the patient an effective amount of a BCMA antigen binding protein if the patient has a high level of soluble BCMA expression.
8. The method of claim 7, wherein the level of soluble BCMA expression in said sample is high when the level of soluble BCMA is above about 10 ng/ml.
9. A method for selecting a dose of BCMA antigen binding protein for treating cancer in a patient in need thereof comprising:
(a) obtaining a sample from the patient;
(b) testing said sample for soluble BCMA expression levels; and is
(c) Treating the patient with a low dose of BCMA antigen binding protein if the patient has low levels of soluble BCMA expression; alternatively, if the patient has a high level of soluble BCMA expression, treating the patient with a high dose of BCMA antigen binding protein.
10. A method of diagnosing cancer in a patient, comprising: (a) obtaining a sample from the patient; and (b) testing said sample for the presence of soluble BCMA expression.
11. The method of any one of the preceding claims, wherein the patient is a human patient.
12. The method of claims 1-3 and 6-10, wherein the cancer is selected from the group consisting of: multiple myeloma, lymphoma, chronic lymphocytic leukemia, non-hodgkin's lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma.
13. The method of claims 1-3 and 6-10, wherein the cancer is multiple myeloma, lymphoma.
14. The method of any one of the preceding claims, wherein the sample is a serum or blood sample.
15. The method of claims 3,4, 6-9, wherein the BCMA antigen binding protein is an antibody, antibody fragment, bispecific antibody, antibody-drug-conjugate, bispecific T cell binding agent (BITE), or chimeric antigen receptor T cells (CAR-T).
16. The method of claim 15, wherein said BCMA antigen binding protein is a monoclonal antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID No. 7; and a VL comprising the amino acid sequence set forth in SEQ ID NO 8, wherein the antibody is conjugated to MMAF.
17. The method of claims 6-9, wherein the patient is further treated with at least one additional anti-neoplastic agent.
18. The method of claim 17, wherein the at least one additional neoplastic agent is selected from the group consisting of: anti-PD 1 antibodies, anti-ICOS antibodies and anti-OX 40 antibodies, anti-CD 38 antibodies, proteasome inhibitors, thalidomide analogs, and dexamethasone.
A BCMA antigen binding protein for use in treating cancer in a patient, wherein the patient is characterized by high levels of soluble BCMA expression in a sample from the patient.
A BCMA antigen binding protein for use in treating cancer in a patient, wherein the patient expresses soluble BCMA in a sample from the patient.
21. The antigen binding protein of claim 19 or 20, wherein the antigen binding protein is an antibody, an antibody fragment, a bispecific antibody, an antibody-drug-conjugate, a bispecific T cell binding agent (BITE), or a chimeric antigen receptor T cell (CAR-T).
22. The antigen binding protein of claim 21, wherein the antigen binding protein is a monoclonal antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID No. 7; and a VL comprising the amino acid sequence set forth in SEQ ID NO 8, wherein the antibody is conjugated to MMAF.
23. A pharmaceutical composition comprising a BCMA antigen binding protein and at least one pharmaceutically acceptable excipient for use in treating cancer in a patient, wherein the patient is characterized by high levels of soluble BCMA expression in a sample from the patient.
24. A pharmaceutical composition comprising a BCMA antigen binding protein and at least one pharmaceutically acceptable excipient for use in treating cancer in a patient, wherein the patient expresses soluble BCMA in a sample from the patient.
25. The pharmaceutical composition of claim 23 or 24, wherein the antigen binding protein is an antibody, an antibody fragment, a bispecific antibody, an antibody-drug-conjugate, a bispecific T cell binding agent (BITE), or a chimeric antigen receptor T cell (CAR-T).
26. The pharmaceutical composition of claim 25, wherein the antigen binding protein is a monoclonal antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID No. 7; and a VL comprising the amino acid sequence set forth in SEQ ID NO 8, wherein the antibody is conjugated to MMAF.
27. A kit for treating cancer with a BCMA antigen binding protein in a patient comprising means for determining the level of soluble BCMA in a sample from said patient.
Use of a BCMA antigen binding protein in the manufacture of a medicament for treating cancer in a patient, wherein a sample obtained from the patient is determined to express soluble BCMA.
Use of a BCMA antigen binding protein in the manufacture of a medicament for treating cancer in a patient, wherein a sample obtained from the patient is determined to have high levels of soluble BCMA expression.
30. The use of claim 28 or 29, wherein the antigen binding protein is an antibody, an antibody fragment, a bispecific antibody, an antibody-drug-conjugate, a bispecific T cell binding agent (BITE), or a chimeric antigen receptor T cell (CAR-T).
31. The use of claim 30, wherein the antigen binding protein is a monoclonal antibody comprising a VH comprising the amino acid sequence set forth in SEQ ID No. 7; and a VL comprising the amino acid sequence set forth in SEQ ID NO 8, wherein the antibody is conjugated to MMAF.
32. A method for treating cancer in a patient in need thereof, comprising determining whether the patient expresses soluble BCMA, wherein if the patient is determined to express soluble BCMA, administering an effective amount of BCMA antigen binding protein to the patient.
33. A method for treating cancer in a patient in need thereof, comprising determining whether the patient expresses high levels of soluble BCMA, wherein if the patient is determined to express high levels of soluble BCMA, administering to the patient an effective amount of BCMA antigen binding protein.
CN201980070604.4A 2018-10-31 2019-10-29 Methods of treating cancer Pending CN112955748A (en)

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